title: A novel aldehyde dehydrogenase-3 activator (Alda-89) protects submandibular gland function from irradiation without accelerating tumor growth.
abstract: OBJECTIVE
  To determine the effect of Alda-89 (an ALDH3 activitor) on (i) the function of irradiated (radiotherapy) submandibular gland (SMG) in mice, (ii) its toxicity profile, and (iii) its effect on the growth of head and neck cancer (HNC) in vitro and in vivo.
  
  
  METHODS
  Adult mice were infused with Alda-89 or vehicle before, during, and after radiotherapy. Saliva secretion was monitored weekly. Hematology, metabolic profile, and postmortem evaluation for toxicity were examined at the time of sacrifice. Alda-89 or vehicle was applied to HNC cell lines in vitro, and severe combined immunodeficient (SCID) mice transplanted with HNC in vivo with or without radiation; HNC growth was monitored. The ALDH3A1 and ALDH3A2 protein expression was evaluated in 89 patients with HNC and correlated to freedom from relapse (FFR) and overall survival (OS).
  
  
  RESULTS
  Alda-89 infusion significantly resulted in more whole saliva production and a higher percentage of preserved acini after radiotherapy compared with vehicle control. There was no difference in the complete blood count, metabolic profile, and major organ morphology between the Alda-89 and vehicle groups. Compared with vehicle control, Alda-89 treatment neither accelerated HNC cell proliferation in vitro, nor did it affect tumor growth in vivo with or without radiotherapy. Higher expression of ALDH3A1 or ALDH3A2 was not significantly associated with worse FFR or OS in either human papillomavirus (HPV)-positive or HPV-negative group.
  
  
  CONCLUSIONS
  Alda-89 preserves salivary function after radiotherapy without affecting HNC growth or causing measurable toxicity in mice. It is a promising candidate to mitigate radiotherapy-related xerostomia.
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Xiao
authors.forename: Hongbin
authors.initials: H
authors.lastname: Cao
authors.forename: Che-Hong
authors.initials: CH
authors.lastname: Chen
authors.forename: Christina S
authors.initials: CS
authors.lastname: Kong
authors.forename: Rehan
authors.initials: R
authors.lastname: Ali
authors.forename: Cato
authors.initials: C
authors.lastname: Chan
authors.forename: Davud
authors.initials: D
authors.lastname: Sirjani
authors.forename: Edward
authors.initials: E
authors.lastname: Graves
authors.forename: Albert
authors.initials: A
authors.lastname: Koong
authors.forename: Amato
authors.initials: A
authors.lastname: Giaccia
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
authors.forename: Quynh-Thu
authors.initials: QT
authors.lastname: Le
mesh_terms: D000328:Adult; D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000445:Aldehyde Oxidoreductases / Q000378:metabolism; D000498:Allyl Compounds / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology* / Q000633:toxicity; D004195:Disease Models, Animal; D020536:Enzyme Activators / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011837:Radiation-Protective Agents / Q000494:pharmacology* / Q000633:toxicity; D013363:Submandibular Gland / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects
chemical_list: C571663:5-allyl-1,3-benzodioxol; D000498:Allyl Compounds; D052117:Benzodioxoles; D020536:Enzyme Activators; D011837:Radiation-Protective Agents; D000445:Aldehyde Oxidoreductases; C480021:ALDH3A1 protein, human; D000444:Aldehyde Dehydrogenase; C038828:long-chain-aldehyde dehydrogenase